Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

Abstract

Purpose: We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease.

Patients and methods: Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m(2), 50 mg/m(2), or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes.

Results: The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma.

Conclusion: Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.

Trial registration: ClinicalTrials.gov NCT01896505.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

(A) Effect of food on the exposure (area under the curve [AUC]) of selinexor as a function of time (0 to 24 hours). Plasma concentration of selinexor (first-generation tablet or capsule; 30 mg/m2) over 24 hours when administered under fasting conditions or in conjunction with a low- or high-fat meal (cohort one). AUCs for all fed conditions were significantly higher compared with that for the fasting state (P < .05). (B) Effect of formulation on the exposure (AUC) of selinexor as a function of time (0 to 48 hours). Comparison of selinexor (60 mg) pharmacokinetics for first- and second-generation tablets and oral suspension over 48 hours (cohort three).

Fig 2.

(A) Percent change in target lesion size from baseline for 47 evaluable patients. Quantitative target lesion assessment was not available for seven patients because of consent withdrawal (n = 2), disease progression based solely on clinical symptoms (n = 4), and death resulting from progressive disease (n = 1), all of which occurred before first post-treatment scan. Bars falling between the dotted lines at 20% and −30% represent stable disease, whereas above 20% represents progressive disease, as determined by RECIST (version 1.1). (B) Time in study for all patients coded by sarcoma subtype. As of the date of data cutoff, two patients continued to receive selinexor treatment. DD, dedifferentiated; LPS, liposarcoma; UPS, undifferentiated pleomorphic sarcoma; WD, well differentiated.

Fig 3.

Radiographic images of antitumor activity in liposarcoma. (A) Baseline computed tomography (CT) scan of a target lesion in an 88-year-old man with advanced refractory dedifferentiated liposarcoma and (B) reduction in tumor size after two cycles of selinexor. (C) Baseline CT scan of a representative lesion in a 72-year-old woman with aggressive dedifferentiated liposarcoma and (D) reduction in tumor size after two cycles of selinexor. Green lines indicate lesion.

Fig 4.

Patient tumor biopsies were analyzed by immunohistochemistry for morphologic and biochemical changes in response to selinexor treatment. (A, B) Hematoxylin and eosin (HE) and (C, D) Masson’s trichrome staining of tumor samples taken from a patient with well-differentiated (WD)/dedifferentiated (DD) liposarcoma at baseline and 4 weeks after receiving selinexor 50 mg/m2. Immunohistochemical staining (brown) of markers for (E, F) proliferation, (G, H) apoptosis, (I, J) XPO1, and (K to P) XPO1 cargo tumor suppressor proteins are also shown. Ki67 staining is from the same patient in panels A to D. ApopTag, p21, and p53 images are from a patient with WD/DD liposarcoma treated with selinexor 60 mg for 4 weeks. XPO1 and FOXO1 images are from a patient with leiomyosarcoma treated with selinexor 30 mg/m2 for 3 weeks. All three patients had a best response of stable disease.

Fig A1.

Schematic of trial design. Arrows indicate selinexor treatment (Monday and Wednesday).

Fig A2.

Time to disease progression (TTP) with selinexor versus TTP with last prior therapy for 41 evaluable patients. Dotted line represents greater than 1.3-fold increase in TTP with selinexor. Thirteen patients were not evaluable because of lack of prior therapy (n = 4) and not having a documented date of disease progression with last prior therapy (n = 9). DD, dedifferentiated; VEGFR, vascular endothelial growth factor receptor; WD, well differentiated.

Fig A3.

Histopathologic evaluation of liposarcoma biopsies. Tumor biopsies from five patients with liposarcoma were collected at baseline or during week 3 or 4 of selinexor treatment and were evaluated by a blinded histopathologist for changes in cell-to-stroma ratio, percent necrosis, and percent Ki67-positive tumor cells. HE, hematoxylin and eosin.